Extensive replication of the human immunodeficiency virus type 1 (HIV-1) in infected individuals ultimately results in clinical manifestation of AIDS. The long-term application of current anti-HIV drugs (anti-protease and anti-reverse transcriptase) has been limited by the development of drug resistance, resulting from rapid mutations in the viral genome RNA. This circumstance has highlighted the need to identify targets and strategies that avoid the effects of mutations. One especially promising HIV target is the nucleocapsid protein, NCp7, which in the mature virion, is closely associated with viral genomic RNA. The nucleocapsid proteins of all lenti- and onco-retroviruses contain one or two copies of the zinc finger motif, Cys-(Xaa)2-Cys-(Xaa)4-His-(Xaa)4-Cys, which are essential for binding and controlling the expression of genomic RNA and are absolutely conserved. Consequently, drug resistance should be much less likely to develop for compounds that disrupt the nucleocapsid- RNA structure. Several disulfide benzamides have been shown to eject HIV-1 NCp7 zinc from purified virions and to possess anti-retroviral activity in cell cultures at low micromolar concentrations. However, in vivo, these compounds have shown various limitations, such as low bioavailability and rapid plasma clearance. In our recent work, we have sought to depart from these chemotypes and synthesized over 160 compounds that are patterned after or depart from the known active dithiobis (benzamides). Nine entirely new SH-reactive groups have been linked to approximately 17 ligand moieties, some of which were based on novel diphenylsulfone structures. These candidate drugs have been screened in a battery of in vitro assays, resulting in the finding of promising new leads. These new leads are very encouraging because they include the first zinc-finger reactive agents given a "confirmed active" designation by NCI that are not disulfides. Two of these compounds, which are sulfur-targeted, acyl transfer agents have so far passed all NCI tests. They show therapeutic indices of 51 and 38, respectively, with no observable cellular toxicity. Interestingly, these compounds are moderate zinc ejectors and are inactive against integrase, protease, cell attachment, and reverse transcriptase using the rCdG or rAdT primer/template system. More importantly, they are active against U1 cells, demonstrating that the antiviral activity is directed not only against acutely infected cells but also against latently infected cells. At the present, studies aimed at increasing our understanding of the NCp7-RNA complex structure are in progress. This knowledge will be essential for formulating the mechanism of action of the new compounds that we have synthesized, and will serve as the basis for the design of better inhibitors of nucleocapsid-dependent virion processing. AIDS title: Structural Studies of Protein-Ligand Complexes to Design New Antiviral Drugs.